A novel common variant in DCST2 is associated with length in early life and height in adulthood

Ralf J P van der Valk; Eskil Kreiner-Møller; Marjolein N Kooijman; Mònica Guxens; Evangelia Stergiakouli; Annika Sääf; Jonathan P Bradfield; Frank Geller; M Geoffrey Hayes; Diana L Cousminer; Antje Körner; Elisabeth Thiering; John A Curtin; Ronny Myhre; Ville Huikari; Raimo Joro; Marjan Kerkhof; Nicole M Warrington; Niina Pitkänen; Ioanna Ntalla; Momoko Horikoshi; Riitta Veijola; Rachel M Freathy; Yik-Ying Teo; Sheila J Barton; David M Evans; John P Kemp; Beate St Pourcain; Susan M Ring; George Davey Smith; Anna Bergström; Inger Kull; Hakon Hakonarson; Frank D Mentch; Hans Bisgaard; Bo Chawes; Jakob Stokholm; Johannes Waage; Patrick Eriksen; Astrid Sevelsted; Mads Melbye; Cornelia M van Duijn; Carolina Medina-Gomez; Albert Hofman; Johan C de Jongste; H Rob Taal; André G Uitterlinden; Loren L Armstrong; Tune H Pers; Klaus Bønnelykke; Early Genetics and Lifecourse Epidemiology (EAGLE) Consortium

doi:10.1093/hmg/ddu510

A novel common variant in DCST2 is associated with length in early life and height in adulthood

Ralf J P van der Valk, Eskil Kreiner-Møller, Marjolein N Kooijman, Mònica Guxens, Evangelia Stergiakouli, Annika Sääf, Jonathan P Bradfield, Frank Geller, M Geoffrey Hayes, Diana L Cousminer, Antje Körner, Elisabeth Thiering, John A Curtin, Ronny Myhre, Ville Huikari, Raimo Joro, Marjan Kerkhof, Nicole M Warrington, Niina Pitkänen, Ioanna NtallaMomoko Horikoshi, Riitta Veijola, Rachel M Freathy, Yik-Ying Teo, Sheila J Barton, David M Evans, John P Kemp, Beate St Pourcain, Susan M Ring, George Davey Smith, Anna Bergström, Inger Kull, Hakon Hakonarson, Frank D Mentch, Hans Bisgaard, Bo Chawes, Jakob Stokholm, Johannes Waage, Patrick Eriksen, Astrid Sevelsted, Mads Melbye, Cornelia M van Duijn, Carolina Medina-Gomez, Albert Hofman, Johan C de Jongste, H Rob Taal, André G Uitterlinden, Loren L Armstrong, Tune H Pers, Klaus Bønnelykke, Early Genetics and Lifecourse Epidemiology (EAGLE) Consortium

59 Citations (Scopus)

Abstract

Common genetic variants have been identified for adult height, but not much is known about the genetics of skeletal growth in early life. To identify common genetic variants that influence fetal skeletal growth, we meta-analyzed 22 genome-wide association studies (Stage 1; N = 28 459). We identified seven independent top single nucleotide polymorphisms (SNPs) (P < 1 × 10^-6) for birth length, of which three were novel and four were in or near loci known to be associated with adult height (LCORL, PTCH1, GPR126 and HMGA2). The three novel SNPs were followed-up in nine replication studies (Stage 2; N = 11 995), with rs905938 in DC-STAMP domain containing 2 (DCST2) genome-wide significantly associated with birth length in a joint analysis (Stages 1 + 2; β = 0.046, SE = 0.008, P = 2.46 × 10^-8, explained variance = 0.05%). Rs905938 was also associated with infant length (N = 28 228; P = 5.54 × 10^-4) and adult height (N = 127 513; P = 1.45 × 10^-5). DCST2 is a DC-STAMP-like protein family member and DC-STAMP is an osteoclast cell-fusion regulator. Polygenic scores based on 180 SNPs previously associated with human adult stature explained 0.13% of variance in birth length. The same SNPs explained 2.95% of the variance of infant length. Of the 180 known adult height loci, 11 were genome-wide significantly associated with infant length (SF3B4, LCORL, SPAG17, C6orf173, PTCH1, GDF5, ZNFX1, HHIP, ACAN, HLA locus and HMGA2). This study highlights that common variation in DCST2 influences variation in early growth and adult height.

Original language	English
Journal	Human Molecular Genetics
Volume	24
Issue number	4
Pages (from-to)	1155-68
Number of pages	14
ISSN	0964-6906
DOIs	https://doi.org/10.1093/hmg/ddu510
Publication status	Published - 15 Feb 2015

Keywords

Adaptor Proteins, Signal Transducing
Adult
Age Factors
Alleles
Body Height
Computational Biology
Databases, Genetic
Genetic Association Studies
Genetic Variation
Genotype
Humans
Infant, Newborn
Membrane Proteins
Phenotype
Polymorphism, Single Nucleotide
Quantitative Trait Loci
Quantitative Trait, Heritable
Reproducibility of Results

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van der Valk, R. J. P., Kreiner-Møller, E., Kooijman, M. N., Guxens, M., Stergiakouli, E., Sääf, A., Bradfield, J. P., Geller, F., Hayes, M. G., Cousminer, D. L., Körner, A., Thiering, E., Curtin, J. A., Myhre, R., Huikari, V., Joro, R., Kerkhof, M., Warrington, N. M., Pitkänen, N., ... Early Genetics and Lifecourse Epidemiology (EAGLE) Consortium (2015). A novel common variant in DCST2 is associated with length in early life and height in adulthood. Human Molecular Genetics, 24(4), 1155-68. https://doi.org/10.1093/hmg/ddu510

van der Valk, RJP, Kreiner-Møller, E, Kooijman, MN, Guxens, M, Stergiakouli, E, Sääf, A, Bradfield, JP, Geller, F, Hayes, MG, Cousminer, DL, Körner, A, Thiering, E, Curtin, JA, Myhre, R, Huikari, V, Joro, R, Kerkhof, M, Warrington, NM, Pitkänen, N, Ntalla, I, Horikoshi, M, Veijola, R, Freathy, RM, Teo, Y-Y, Barton, SJ, Evans, DM, Kemp, JP, St Pourcain, B, Ring, SM, Davey Smith, G, Bergström, A, Kull, I, Hakonarson, H, Mentch, FD, Bisgaard, H, Chawes, B, Stokholm, J, Waage, J, Eriksen, P, Sevelsted, A, Melbye, M, van Duijn, CM, Medina-Gomez, C, Hofman, A, de Jongste, JC, Taal, HR, Uitterlinden, AG, Armstrong, LL, Pers, TH , Bønnelykke, K & Early Genetics and Lifecourse Epidemiology (EAGLE) Consortium 2015, 'A novel common variant in DCST2 is associated with length in early life and height in adulthood', Human Molecular Genetics, vol. 24, no. 4, pp. 1155-68. https://doi.org/10.1093/hmg/ddu510

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title = "A novel common variant in DCST2 is associated with length in early life and height in adulthood",

abstract = "Common genetic variants have been identified for adult height, but not much is known about the genetics of skeletal growth in early life. To identify common genetic variants that influence fetal skeletal growth, we meta-analyzed 22 genome-wide association studies (Stage 1; N = 28 459). We identified seven independent top single nucleotide polymorphisms (SNPs) (P < 1 × 10-6) for birth length, of which three were novel and four were in or near loci known to be associated with adult height (LCORL, PTCH1, GPR126 and HMGA2). The three novel SNPs were followed-up in nine replication studies (Stage 2; N = 11 995), with rs905938 in DC-STAMP domain containing 2 (DCST2) genome-wide significantly associated with birth length in a joint analysis (Stages 1 + 2; β = 0.046, SE = 0.008, P = 2.46 × 10-8, explained variance = 0.05%). Rs905938 was also associated with infant length (N = 28 228; P = 5.54 × 10-4) and adult height (N = 127 513; P = 1.45 × 10-5). DCST2 is a DC-STAMP-like protein family member and DC-STAMP is an osteoclast cell-fusion regulator. Polygenic scores based on 180 SNPs previously associated with human adult stature explained 0.13% of variance in birth length. The same SNPs explained 2.95% of the variance of infant length. Of the 180 known adult height loci, 11 were genome-wide significantly associated with infant length (SF3B4, LCORL, SPAG17, C6orf173, PTCH1, GDF5, ZNFX1, HHIP, ACAN, HLA locus and HMGA2). This study highlights that common variation in DCST2 influences variation in early growth and adult height.",

keywords = "Adaptor Proteins, Signal Transducing, Adult, Age Factors, Alleles, Body Height, Computational Biology, Databases, Genetic, Genetic Association Studies, Genetic Variation, Genotype, Humans, Infant, Newborn, Membrane Proteins, Phenotype, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Quantitative Trait, Heritable, Reproducibility of Results",

author = "{van der Valk}, {Ralf J P} and Eskil Kreiner-M{\o}ller and Kooijman, {Marjolein N} and M{\`o}nica Guxens and Evangelia Stergiakouli and Annika S{\"a}{\"a}f and Bradfield, {Jonathan P} and Frank Geller and Hayes, {M Geoffrey} and Cousminer, {Diana L} and Antje K{\"o}rner and Elisabeth Thiering and Curtin, {John A} and Ronny Myhre and Ville Huikari and Raimo Joro and Marjan Kerkhof and Warrington, {Nicole M} and Niina Pitk{\"a}nen and Ioanna Ntalla and Momoko Horikoshi and Riitta Veijola and Freathy, {Rachel M} and Yik-Ying Teo and Barton, {Sheila J} and Evans, {David M} and Kemp, {John P} and {St Pourcain}, Beate and Ring, {Susan M} and {Davey Smith}, George and Anna Bergstr{\"o}m and Inger Kull and Hakon Hakonarson and Mentch, {Frank D} and Hans Bisgaard and Bo Chawes and Jakob Stokholm and Johannes Waage and Patrick Eriksen and Astrid Sevelsted and Mads Melbye and {van Duijn}, {Cornelia M} and Carolina Medina-Gomez and Albert Hofman and {de Jongste}, {Johan C} and Taal, {H Rob} and Uitterlinden, {Andr{\'e} G} and Armstrong, {Loren L} and Pers, {Tune H} and Klaus B{\o}nnelykke and {Early Genetics and Lifecourse Epidemiology (EAGLE) Consortium}",

year = "2015",

month = feb,

day = "15",

doi = "10.1093/hmg/ddu510",

language = "English",

volume = "24",

pages = "1155--68",

journal = "Human Molecular Genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

number = "4",

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TY - JOUR

T1 - A novel common variant in DCST2 is associated with length in early life and height in adulthood

AU - van der Valk, Ralf J P

AU - Kreiner-Møller, Eskil

AU - Kooijman, Marjolein N

AU - Guxens, Mònica

AU - Stergiakouli, Evangelia

AU - Sääf, Annika

AU - Bradfield, Jonathan P

AU - Geller, Frank

AU - Hayes, M Geoffrey

AU - Cousminer, Diana L

AU - Körner, Antje

AU - Thiering, Elisabeth

AU - Curtin, John A

AU - Myhre, Ronny

AU - Huikari, Ville

AU - Joro, Raimo

AU - Kerkhof, Marjan

AU - Warrington, Nicole M

AU - Pitkänen, Niina

AU - Ntalla, Ioanna

AU - Horikoshi, Momoko

AU - Veijola, Riitta

AU - Freathy, Rachel M

AU - Teo, Yik-Ying

AU - Barton, Sheila J

AU - Evans, David M

AU - Kemp, John P

AU - St Pourcain, Beate

AU - Ring, Susan M

AU - Davey Smith, George

AU - Bergström, Anna

AU - Kull, Inger

AU - Hakonarson, Hakon

AU - Mentch, Frank D

AU - Bisgaard, Hans

AU - Chawes, Bo

AU - Stokholm, Jakob

AU - Waage, Johannes

AU - Eriksen, Patrick

AU - Sevelsted, Astrid

AU - Melbye, Mads

AU - van Duijn, Cornelia M

AU - Medina-Gomez, Carolina

AU - Hofman, Albert

AU - de Jongste, Johan C

AU - Taal, H Rob

AU - Uitterlinden, André G

AU - Armstrong, Loren L

AU - Pers, Tune H

AU - Bønnelykke, Klaus

AU - Early Genetics and Lifecourse Epidemiology (EAGLE) Consortium

PY - 2015/2/15

Y1 - 2015/2/15

N2 - Common genetic variants have been identified for adult height, but not much is known about the genetics of skeletal growth in early life. To identify common genetic variants that influence fetal skeletal growth, we meta-analyzed 22 genome-wide association studies (Stage 1; N = 28 459). We identified seven independent top single nucleotide polymorphisms (SNPs) (P < 1 × 10-6) for birth length, of which three were novel and four were in or near loci known to be associated with adult height (LCORL, PTCH1, GPR126 and HMGA2). The three novel SNPs were followed-up in nine replication studies (Stage 2; N = 11 995), with rs905938 in DC-STAMP domain containing 2 (DCST2) genome-wide significantly associated with birth length in a joint analysis (Stages 1 + 2; β = 0.046, SE = 0.008, P = 2.46 × 10-8, explained variance = 0.05%). Rs905938 was also associated with infant length (N = 28 228; P = 5.54 × 10-4) and adult height (N = 127 513; P = 1.45 × 10-5). DCST2 is a DC-STAMP-like protein family member and DC-STAMP is an osteoclast cell-fusion regulator. Polygenic scores based on 180 SNPs previously associated with human adult stature explained 0.13% of variance in birth length. The same SNPs explained 2.95% of the variance of infant length. Of the 180 known adult height loci, 11 were genome-wide significantly associated with infant length (SF3B4, LCORL, SPAG17, C6orf173, PTCH1, GDF5, ZNFX1, HHIP, ACAN, HLA locus and HMGA2). This study highlights that common variation in DCST2 influences variation in early growth and adult height.

AB - Common genetic variants have been identified for adult height, but not much is known about the genetics of skeletal growth in early life. To identify common genetic variants that influence fetal skeletal growth, we meta-analyzed 22 genome-wide association studies (Stage 1; N = 28 459). We identified seven independent top single nucleotide polymorphisms (SNPs) (P < 1 × 10-6) for birth length, of which three were novel and four were in or near loci known to be associated with adult height (LCORL, PTCH1, GPR126 and HMGA2). The three novel SNPs were followed-up in nine replication studies (Stage 2; N = 11 995), with rs905938 in DC-STAMP domain containing 2 (DCST2) genome-wide significantly associated with birth length in a joint analysis (Stages 1 + 2; β = 0.046, SE = 0.008, P = 2.46 × 10-8, explained variance = 0.05%). Rs905938 was also associated with infant length (N = 28 228; P = 5.54 × 10-4) and adult height (N = 127 513; P = 1.45 × 10-5). DCST2 is a DC-STAMP-like protein family member and DC-STAMP is an osteoclast cell-fusion regulator. Polygenic scores based on 180 SNPs previously associated with human adult stature explained 0.13% of variance in birth length. The same SNPs explained 2.95% of the variance of infant length. Of the 180 known adult height loci, 11 were genome-wide significantly associated with infant length (SF3B4, LCORL, SPAG17, C6orf173, PTCH1, GDF5, ZNFX1, HHIP, ACAN, HLA locus and HMGA2). This study highlights that common variation in DCST2 influences variation in early growth and adult height.

KW - Adaptor Proteins, Signal Transducing

KW - Adult

KW - Age Factors

KW - Alleles

KW - Body Height

KW - Computational Biology

KW - Databases, Genetic

KW - Genetic Association Studies

KW - Genetic Variation

KW - Genotype

KW - Humans

KW - Infant, Newborn

KW - Membrane Proteins

KW - Phenotype

KW - Polymorphism, Single Nucleotide

KW - Quantitative Trait Loci

KW - Quantitative Trait, Heritable

KW - Reproducibility of Results

U2 - 10.1093/hmg/ddu510

DO - 10.1093/hmg/ddu510

M3 - Journal article

C2 - 25281659

SN - 0964-6906

VL - 24

SP - 1155

EP - 1168

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 4

ER -

A novel common variant in DCST2 is associated with length in early life and height in adulthood

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Keywords

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